Downregulation of GSTK1 Is a Common Mechanism Underlying Hypertrophic Cardiomyopathy

Nishimura Yuhei, Sasagawa Shota, Okabe Shiko, Murakami Soichiro, Ashikawa Yoshifumi, Yuge Mizuki, Kawaguchi Koki, Kawase Reiko, Okamoto Ryuji, Ito Masaaki, TANAKA TOSHIO; Front. Pharmacol., 14 June 2016, doi:10.3389/fphar.2016.00162

Open-access (article distributed under the terms of the Creative Commons Attribution License).

 HCM has multiple etiologies, including mutation in sarcomeric genes such as myosin heavy chain 7 (MYH7) and tropomyosin 1 (TPM1) and in non-sarcomeric genes such as PLN and FXN.Haploinsufficiency of FXN is a major cause of FA. FA is associated with progressive HCM, and this is a common cause of death in FA patients. FXN is an iron-binding protein targeted to the mitochondrial matrix, and consistent with this, mitochondrial function is impaired in FA.  Comparative transcriptomics could represent a new frontier in the search for novel biomarkers and/or therapeutic targets in diseases with multiple etiologies because it facilitates the identification of dysregulated genes common to all disease etiologie. We identified five genes dysregulated in all five HCM transcriptome datasets, among which glutathione S-transferase kappa 1 (Gstk1) was the only gene downregulated. We demonstrate here that knockout of gstk1 in zebrafish increased the expression of HCM marker genes and decreased the cardiac EDV and, to a lesser extent, the ESV, suggesting that downregulation of GSTK1 may be a common mechanism underlying HCM of various etiologies.

Big Data in medical research and EU data protection law: challenges to the consent or anonymise approach

Mostert M, Bredenoord AL, Biesaart MC, van Delden JJ., European Journal of Human Genetics (2016) 24, 956–960; doi:10.1038/ejhg.2015.239; published online 11 November 2015

In recent years, both medical research and the legal landscape have been changing as a result of the rapid developments in information technology (IT). Medical researchers are collecting, re-using and linking health-related and genomic data on an unprecedented scale, based on the presupposition that this research will significantly improve human health. Developments in IT have however led to an increasing concern about the effectiveness of existing data protection law, and the need for a more consistent and comprehensive protection of personal data was recognised in the European Union (EU).

The role of R-loops in the pathology of trinucleotide expansion diseases

Matthias Groh, Natalia Gromak (Supervisor), Thesis, ORA Oxford University Research Archive

Friedreich ataxia and fragile X syndrome are among 40 human diseases associated with expansion of repeated DNA sequences. In both disorders repeat expansion leads to gene silencing, the molecular mechanism of which is not well understood.

Vestibulo-ocular reflex dynamics with head-impulses discriminates spinocerebellar ataxias types 1, 2 and 3 and Friedreich ataxia

Luis, L., Costa, J., Muñoz, E., de Carvalho, M., Carmona, S., Schneider, E., Gordon, C.R., Valls-Solé, J.; Journal of Vestibular Research, vol. 26, no. 3, pp. 327-334, 2016, DOI: 10.3233/VES-160579

Although the diagnosis of inherited ataxias is ultimately genetic, this usually means an extensive and expensive process. This justifies the search for distinct clinical signs that may potentially help orient molecular diagnosis. A correlation between VOR and SARA raises the possibility of using VOR gain as a neurophysiologic biomarker for disease severity.

Friedreich’s ataxia and Advanced Heart Failure: An Ethical Conundrum in Decision Making

Peter Ivak, Alena Zumrová, Ivan Netuka, The Journal of Heart and Lung Transplantation, Available online 7 July 2016, ISSN 1053-2498, doi:10.1016/j.healun.2016.06.021

The postoperative course was uneventful and allograft function remained without rejection with preserved function through the follow-up at 100 months. Notably, her neurological status improved and at 8 years stabilized with favorable scores compared to pre-transplant baseline.

 Heart transplant; dilated cardiomyopathy

Deuterium switcheroo breathes life into old drugs

Bethany Halford, Chemical & Engineering News, Volume 94 Issue 27 pp. 32-36 Issue Date: July 4, 2016

Drugmakers juggle isotopes in hopes of achieving novelty, stability, and success. Heavier than hydrogen by a single neutron, deuterium might not seem to have much chemical heft. But the small matter of that subatomic particle makes a massive difference in the reactivity of hydrogen versus its isotope deuterium.

Currently in Friedreich ataxia's Research Pipeline: RT001 (RETROTOPE).


The strategy here is to stabilize the PUFAs and protect the cells from this oxidative damage. One approach to stabilizing the PUFAs is to create mimetics (very similar chemical substitutes) of PUFAs. Retrotope filed their IND with FDA in 2015 and announced enrollment of a 28-day, first-in-human, randomized, double-blind, controlled, ascending dose study of orally dosed RT001 to evaluate the safety, tolerability, pharmacokinetics (PK), disease state, and exploratory endpoints in patients with Friedreich’s ataxia (FA) in August 2015. This study is taking place at University of South Florida and University of California Los Angeles.

Genetic testing in neurology

Henrietta Lefroy, Victoria Harrison, Andrea H. Németh, Medicine, Available online 25 June 2016, ISSN 1357-3039, doi:10.1016/j.mpmed.2016.05.006.

Keywords: Carrier testing; confidentiality; consent; diagnostic testing; genetic testing; neurogenetics; neurology; next-generation sequencing; pre-symptomatic testing

Characteristics of patients contacting a center for undiagnosed and rare diseases

Tobias Mueller, Andreas Jerrentrup, Max Jakob Bauer, Hans Walter Fritsch and Juergen Rolf Schaefer. Orphanet Journal of Rare Diseases201611:81 DOI: 10.1186/s13023-016-0467-2

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License

Secondary coenzyme Q10 deficiencies in oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders

Delia Yubero, Raquel Montero, Miguel A. Martín, Julio Montoya, Antonia Ribes, Manuela Grazina, Eva Trevisson, Juan Carlos Rodriguez-Aguilera, Iain P. Hargreaves, Leonardo Salviati, Plácido Navas, Rafael Artuch, Mitochondrion, Available online 30 June 2016, ISSN 1567-7249, http://dx.doi.org/10.1016/j.mito.2016.06.007.

Non-OXPHOS diseases may present with a CoQ deficiency, such as in multiple Acyl-CoA dehydrogenase deficiency (2 patients), apraxia with oculomotor ataxia and Friedreich’s ataxia. However, decreased levels of CoQ seemed not to be a consistent feature in some of these conditions given that patients who had the same disease were found to have both normal or reduced CoQ levels.

Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies

Alessandro Rimessi, Maurizio Previati, Federica Nigro, Mariusz R. Wieckowski, Paolo Pinton, The International Journal of Biochemistry & Cell Biology, Available online 29 June 2016, ISSN 1357-2725, Doi:10.1016/j.biocel.2016.06.015

Open Access funded by Telethon (Italy), Under a Creative Commons license